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  • Gary Birnbaum, MD

What triggers progressive MS?

β-Synuclein-reactive T cells induce autoimmune

CNS grey matter degeneration.

Lodygin D, Hermann M, Schweingruber N, Flügel-Koch C, Watanabe T, Schlosser C, Merlini A, Körner H, Chang HF, Fischer HJ, Reichardt HM, Zagrebelsky M, Mollenhauer B, Kügler S, Fitzner D, Frahm J, Stadelmann C, Haberl M, Odoardi F, Flügel A.

Nature. 2019 Feb;566(7745):503-508. doi: 10.1038/s41586-019-0964-2. Epub 2019 Feb 20. Erratum in: Nature. 2019 Mar;567(7749):E15.

Key Points:

1. As noted in my blog “Double Whammy” there are two very different immune processes going on at the same time in the central nervous systems of persons with relapsing forms of multiple sclerosis.

2. In relapsing forms of multiple sclerosis there are periodic invasions of the central nervous system by circulating immune cells that attack and destroy myelin, the insulation surrounding nerve fibers (called axons), as well as the cells producing myelin, the oligodendrocytes. Eventually axons also are destroyed.

3. In progressive MS there is a more gradual infiltration of different populations of immune cells that enter the brain and remain isolated from the blood without multiplying.

4. They travel to regions of the brain different than cells involved in acute attacks, going to the brain’s cortex or grey matter, where there are mainly nerve cells, and to areas under the brain’s covering (the meninges). There the cells activate other cells in the brain, such as astrocytes, macrophages and microglia, and all secrete toxins that result in the gradual degeneration of myelin, axons, and nerve cells, with scarring and brain shrinkage (atrophy).

5. The stimulus that triggers attacks of acute MS is not known, but there is evidence that attacks result from an immune response to proteins found in myelin, such as myelin basic protein (MBP).

6. The trigger(s) that continue to stimulate cells involved in progressive MS also are not known, but appear to be different than those triggering acute inflammation.

7. Since MS is a disease only of humans, animal models of MS, while useful, do not necessarily reflect what happens in persons. This paper studied immune cells in rats and used two different proteins to stimulate the rat’s immune system, a nerve-cell protein called b-synuclein and the myelin protein MBP.

8. Β-synuclein is one of a family of three synucleins, a, b, and g (alpha, beta, and gamma). The first two are found almost exclusively in nerve cells, mainly around the connections between nerve cell fibers called synapses. There these proteins help in the release of chemicals that allow nerve cells to communicate with one-another.

9. The family of synucleins, especially a-synuclein, has been implicated in several degenerative brain diseases, in particular Parkinson’s disease and dementia with Loewy bodies. In these diseases a-synuclein forms clumps of proteins called “aggregates,” believed to be toxic to nerve cells.

10.a-synuclein aggregates are not seen in MS but mice immunized with β-synuclein develop both acute brain and eye inflammation, a pattern different than that noted in rats, as well as myelin loss.

11.In the paper under discussion investigators stimulated rat immune cells (T cells) with either β-synuclein or MBP. They then injected these cells into rats and tracked both where they went and what they did.

12.Both sets of immune cells entered the brain the same way, using the same chemicals (chemokines) to get into the brain. However, once in the central nervous system cells immunized to β-synuclein went to rat brain cortex or gray matter. T cells immunized to MBP wound up in the spinal cord.

13.Once in the cortex the β-synuclein T cells caused a lot of inflammation, with nerve cell death, brain shrinkage (atrophy), scarring, and tissue degeneration. The animals had weakness of one or another limb and also showed unusual behaviors such as scratching, loss of balance, and turning in circles.

14.Cells immune to MBP went mainly to the rats’ spinal cords, areas with large amounts of myelin. There they induced acute attacks of leg weakness similar to attacks seen in persons with MS.

15.The investigators then studied the immune responses of blood cells from 29 normal individuals, 40 persons with either relapsing forms of multiple sclerosis or secondary progressive MS, as well as 20 persons with Parkinson’s disease.

16.Cells from normal individuals have low-grade immune responses to both β-synuclein and MBP. Persons with relapsing forms of multiple sclerosis also had immune responses to both β-synuclein and MBP, but with much greater numbers of cells responsive to MBP. Persons with progressive MS had the highest numbers of cells responsive to β-synuclein, and the numbers were highest in persons with the longest duration of progressive disease. Responses to MBP were low in persons with progressive disease. Persons with Parkinson’s disease had poor responses to β-synuclein and MBP but high responses to a-synuclein, the protein found clumped in many nerve cells of persons with Parkinson’s disease. Persons with MS also had higher responses to a-synuclein than did normal individuals.

17.While these studies do not prove that β-synuclein triggers disease progression in MS, the observations are important as they are the first evidence that patterns of immune response to brain tissues in persons with acute MS are different than immune responses in persons with progressive MS. If confirmed by other laboratories, these observations could lead to treatments more specific for progressive disease than those currently available (see “Double Whammy” posting).

With increasing knowledge of the cells involved in relapsing forms of multiple sclerosis and progressive MSit has become clear that the triggers of these two simultaneously occurring processes must be different. Many studies of relapsing disease in mice and humans showed that proteins of myelin, such myelin basic protein (MBP), myelin oligodendrocyte protein (MOG), and proteolipid protein (PLP) are important and can cause acute central nervous system inflammation in experimental animals and, accidentally, in humans. However, the trigger(s) of immune responses in progressive forms of MS have been elusive. The paper discussed in this posting is among the first to identify a brain protein that may trigger progressive MS. The protein, β-synuclein, is especially important as it is part of a family of proteins that may also be involved in other brain disease such as Parkinson’s disease and dementia with Loewy bodies. In these illnesses there are clumps of a-synuclein in nerve cells, associated with cell toxicity and nerve cell death. Mild inflammation also is present at these sites. In progressive MS there are no clumps or aggregates of β-synuclein in nerve cells, but the pattern of nerve cell death and tissue scarring is similar.

Many questions still remain to be answered. Is the response to β-synuclein the first or primary reaction in MS, with immune responses to myelin proteins occurring only after there is nerve cell death? While aggressive treatment of relapsing forms of multiple sclerosis reduces the chances of developing progressive disease (see my blog posting “Can progressive MS be prevented?”), what continues to stimulate the progressive immune response? How can disease-modifying therapies specific for the destructive immune system cells and brain cells of progressive MS get into the affected areas since these areas are not usually accessible to circulating medications? While much work still needs to be done, knowing some of the possible triggers of the immune response in progressive MS is a major advance.

The abstract of this article is available.